4KNN

Crystal structure of human carbonic anhydrase isozyme XIII with 2-Chloro-4-[(pyrimidin-2-ylsulfanyl)acetyl]benzenesulfonamide

Summary for 4KNN

• Entry DOI: 10.2210/pdb4knn/pdb
• Related: 4KNI 4KNJ 4KNM 4KP5 4KP8
• Descriptor: Carbonic anhydrase 13, ZINC ION, 2-chloro-4-[(pyrimidin-2-ylsulfanyl)acetyl]benzenesulfonamide, ... (8 entities in total)
• Functional Keywords: drug design, carbonic anhydrase, benzenesulfonamide, metal-binding, lyase-lyase inhibitor complex, lyase/lyase inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 60901.80

Authors

Smirnov, A.,Manakova, E.,Grazulis, S. (deposition date: 2013-05-10, release date: 2013-11-06, Last modification date: 2023-11-08)

Primary citation

Capkauskaite, E.,Zubriene, A.,Smirnov, A.,Torresan, J.,Kisonaite, M.,Kazokaite, J.,Gylyte, J.,Michailoviene, V.,Jogaite, V.,Manakova, E.,Grazulis, S.,Tumkevicius, S.,Matulis, D.
Benzenesulfonamides with pyrimidine moiety as inhibitors of human carbonic anhydrases I, II, VI, VII, XII, and XIII
Bioorg.Med.Chem., 21:6937-6947, 2013

PubMed Abstract: Two groups of benzenesulfonamide derivatives, bearing pyrimidine moieties, were designed and synthesized as inhibitors of carbonic anhydrases (CA). Their binding affinities to six recombinant human CA isoforms I, II, VI, VII, XII, and XIII were determined by the thermal shift assay (TSA). The binding of several inhibitors was measured by isothermal titration calorimetry (ITC). Direct demonstration of compound inhibition was achieved by determining the inhibition constant by stopped-flow CO2 hydration assay. The most potent compounds demonstrated selectivity towards isoform I and affinities of 0.5 nM. The crystal structures of selected compounds in complex with CA II, XII, and XIII were determined to atomic resolution. Compounds described here were compared with previously published pyrimidinebenzenesulfonamides.(1) Systematic structure-activity analysis of 40 compound interactions with six isoforms yields clues for the design of compounds with greater affinities and selectivities towards target CA isoforms.

PubMed: 24103428
DOI: 10.1016/j.bmc.2013.09.029

Experimental method

X-RAY DIFFRACTION (1.404 Å)